Cabazitaxel, (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(Acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-ene-2-yl benzoate, is a microtubule inhibitor which is being investigated for a number of cancer treatments, including head and neck cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), glioma, bladder cancer, gastric and esophageal cancer, breast cancer and ovarian cancer. Cabazitaxel has been specifically designed to overcome multidrug resistance (MDR) associated with paclitaxel and docetaxel and with many other anticancer drugs.
Due to its poor solubility in water, the commercial formulation of cabazitaxel (JEVTANA®) employs polysorbate 80 (a surfactant) as a solubilizer and ethanol as a diluent. Due to the presence of such surfactant and ethanol this formulation requires that a patient be premedicated with an antihistamine, a corticosteroid and an H2 antagonist. Such formulation further requires a two-step preparation process prior to infusion into a patient. In the first step a vial containing cabazitaxel and an excipient must be mixed with another vial containing ethanol; in the second step, this mixed solution is then diluted with saline or 5% dextrose. According to its label, the JEVTANA® dosing solution must be used within eight hours at room temperature, or within 24 hour if refrigerated. Both time limits include infusion time of approximately 1 hour.
Accordingly, it would be desirable to possess a cabazitaxel formulation which exhibited increased stability; which did not require the presence of surfactant and/or ethanol; and which could be prepared in a more simple and convenient process.
While the prior art has proposed the formulation of related compounds, such as docetaxel with substituted cyclodextrins, such formulations still contain ethanol. Thus, for example, Young et al (U.S. Pat. No. 8,481,511) disclose inclusion complexes of docetaxel and hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin in a ratio of 1:10-150. The complexes are prepared as follows: docetaxel dissolved in ethanol is added into water solution of cyclodextrin via stirring, until docetaxel is completely dissolved; said solution is filtered in 0.2-04 μm microporous membrane then ethanol is removed through reduced pressure to obtain the inclusion complex in a liquid form; or ethanol, followed by water is removed through reduced pressure, then dried to obtain the inclusion complex in a solid form. Young et al stress the benefits of the reduced ethanol concentration in their final compositions stating that the “low residual ethanol level provided a favorable guarantee for improving the docetaxel stability and reducing irritation and other side effects”. Consequently, it is unexpected that an improved formulation of cabazitaxel could be prepared using sulfobutyl ether beta cyclodexctrin which formulation did not contain any residual ethanol.